Opioids acting at the mu opioid receptor (MOR) are the most effective therapy for moderate to severe pain, but serious side effects limit their use. Abuse liability is of particular importance. The recent epidemic of opioid abuse has produced major medical, societal and economic problems. Additional side effects include respiratory depression, the cause of fatal overdose, tolerance, which complicates treatment and increases risk of side effects, and motor and cognitive impairment. Despite these and other adverse effects, medications based on compounds discovered around 100 years ago represent a majority of the available opioids. In an innovative approach to the development of pain medications, we developed modifications of a natural brain peptide that resulted in a stable, MOR-selective, highly effective analgesic with a reduction of several side effects relative to morphine. These include reduction in a) respiratory depression, b) impairment of motor coordination, c) tolerance and hyperalgesia, d) glial p38/CGRP/P2X7 receptor signaling, and e) reward/abuse potential in two animal models -conditioned place preference (CPP) and self-administration (SA) tests- that correlate with human abuse liability. In this project we will further characterize the effects of this lead compound, the endomorphin analog ZH853, in tests indicative of abuse liability. These include tests of dependence (indicated by withdrawal symptoms and aversion behaviors), and CPP and SA tests in conditions known to enhance drug- seeking and -taking (previous opioid use and stress). A lack of rewarding properties by ZH853 in these conditions would reinforce the likelihood that it will not be abused in humans and that it would be useful for pain treatment of former addicts. We will also test the possibility that ZH853 could be useful for opioid maintenance therapy for addiction. The latter will be tested in reinstatement paradigms where CPP and SA induced by morphine are extinguished and ZH853 is then tested for reduction/prevention of reinstatement. We will also examine a mechanism likely to contribute to the different, more favorable profile of ZH853: We have shown that ZH853 does not produce the glial activation shown by morphine in the spinal cord and correlated with tolerance. We will assess whether differential glial activation in the brain reward system contributes to the relative lack of reward (that correlates with addiction potential) by ZH853 compared to morphine. Successful outcome of the studies would support the concepts that ZH853: 1) has low abuse liability even under conditions known to enhance the likelihood of drug use (previous opioid use and stress), 2) could safely provide effective pain relief for patients previously addicted to opioids, 3) could provide maintenance therapy for opioid addiction, and 4) is mechanistically distinct from morphine due to its lack of activation of glia and glial-neuron plasticity in the reward system. Together with the previously demonstrated extensive range of reduced side effects, these outcomes would provide evidence that ZH853 could be an ideal candidate for addressing two areas of the highest importance to veterans and the general population: 1) safer and more effective pain relief and 2) reduction of opioid abuse.